Electrochemistry-Enabled Ir-Catalyzed Vinylic C-H Functionalization

Article abstract of DOI:10.1021/jacs.9b11915

Synergistic use of electrochemistry and organometallic catalysis has emerged as a powerful tool for site-selective C-H functionalization, yet this type of transformation has thus far mainly been limited to arene C-H functionalization. Herein, we report the development of electrochemical vinylic C-H functionalization of acrylic acids with alkynes. In this reaction an iridium catalyst enables C-H/O-H functionalization for alkyne annulation, affording α-pyrones with good to excellent yields in an undivided cell. Preliminary mechanistic studies show that anodic oxidation is crucial for releasing the product and regeneration of an Ir(III) intermediate from a diene-Ir(I) complex, which is a coordinatively saturated, 18-electron complex. Importantly, common chemical oxidants such as Ag(I) or Cu(II) did not give significant amounts of the desired product in the absence of electrical current under otherwise identical conditions.

Full text of DOI:10.1021/jacs.9b11915

Subscriber access provided by - Access paid by the | UCSF Library
Communication
Electrochemistry-Enabled Ir-Catalyzed Vinylic C-H Functionalization
Qi-Liang Yang, Yi-Kang Xing, Xiang-Yang Wang, Hong-Xing Ma,
Xin-Jun Weng, Xiang Yang, Hai-Ming Guo, and Tian-Sheng Mei
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11915 • Publication Date (Web): 12 Nov 2019
Downloaded from pubs.acs.org on November 12, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 8
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Electrochemistry-Enabled Ir-Catalyzed Vinylic C−H Functionaliza-
tion
Qi-Liang Yang,†,‡,§ Yi-Kang Xing,†,§ Xiang-Yang Wang,† Hong-Xing Ma,† Xin-Jun Weng,† Xiang
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yang,† Hai-Ming Guo,‡ Tian-Sheng Mei†,*
†State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Insti-
tute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling
Lu, Shanghai, 200032, China
‡Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Collaborative Innovation Center of
Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, He-
nan Normal University, Xinxiang, Henan, 453007, China
Supporting Information Placeholder
izing non-activated C(sp3)–H bonds using quinuclidine as a
ABSTRACT Synergistic use of electrochemistry and or-
redox mediator with moderate site-selectivity.6 In these cases,
ganometallic catalysis has emerged as a powerful tool for
site-selective C–H functionalization, yet this type of trans-
Scheme 1. Electrochemical Vinylic C–H Functionaliza-
formation has thus far mainly been limited to arene C–H
functionalization. Herein, we report the development of
electrochemical vinylic C–H functionalization of acrylic
acids with alkynes. In this reaction an iridium catalyst
enables C–H/O–H functionalization for alkyne annulation,
affording -pyrones with good to excellent yields in an
undivided cell. Preliminary mechanistic studies show that
anodic oxidation is crucial for releasing the product and
regeneration of a Ir(III) intermediate from a diene-Ir(I)
complex, which is a coordinatively saturated, 18-electron
complex. Importantly, common chemical oxidants such
as Ag(I) or Cu(II) did not give significant amounts of the
desired product in the absence of electrical current under
otherwise identical conditions.
tion
secondary or tertiary C–H bonds are preferentially function-
alized over primary C–H bonds. Alternatively, our lab7 and
the Sanford group8 independently developed site-selective
electrochemical C(sp3)–H functionalization by merging with
Pd catalysis, in which primary C–H bonds proximal to a suit-
able directing group are selectively functionalized.9 Similarly,
metal-catalyzed site-selective electrochemical arene C–H
functionalization was also developed with various metal
catalysts, such as Pd,10 Ni,11 Co,12 Ru,13 Cu,14 Rh,15 and Ir.16 In
these systems electric current was used as oxidant to turn
over the catalyst.17,18 Electrochemical vinylic C–H functionali-
zation, however, remains rare.12c,19,20 Generally speaking, elec-
trochemical oxidation of the alkene -bond is much easier
than functionalization a vinylic C–H bond, since the dissocia-
tion energy of the -bond (about 65 kcal/mol) is much lower
than that of the vinylic C–H bond (about 111 kcal/mol)
(Scheme 1A).21 Herein, we report Ir-catalyzed electrochemical
vinylic C–H annulation of acrylic acids with alkynes, afford-
ing various substituted -pyrones (Scheme 1B), which are
ubiquitous motifs found in many natural products and bio-
logical active small molecules.22 Although, vinylic C–H annu-
lations of acrylic acids with alkynes to form -pyrones were
The past decade has witnessed a renaissance in electro-
chemical organic synthesis. This approach utilizes electric
current to replace conventional chemical oxidants or reduct-
ants to drive the reaction, thereby representing an environ-
mentally friendly alternative to traditional approaches.1 More
importantly, in electrochemistry the potential can be precise-
ly controlled, allowing for unique reactivity and chemoselec-
tivity.2 Among many electrochemical transformations, elec-
trochemical C–H functionalization represents one of most
promising reaction types, since this approach not only avoids
prefunctionalization of the substrate but also provides novel
disconnections in retrosynthetic analysis.3 Owing to the
higher oxidation potentials of C–H bonds compared to
common functional groups and organic solvents, mediated
electrochemical oxidation is typically employed.4 For in-
stance, Baran and co-worker recently elegantly developed a
scalable and sustainable electrochemical allylic oxidation
using tetrachloro-N-hydroxyphthalimide (Cl4NHPI) as the
mediator.5 The same group further demonstrated functional-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 8
realized with Co,23 Ru,24 Rh,25 and Pd catalysis,26 the same
tions (entry 14–16). However, 18% yield of 3a was obtained
when PhI(OAc)2 was employed (entry 17). This observation
indicates that the merger of electrochemistry and iridium
catalysis provides unique reactivity in this system. Finally,
control experiments indicated that the Ir catalyst and electric
current are both essential for this reaction (entries 18 and 19).
With the optimized reaction conditions in hand, the sub-
strate scope was investigated to test the generality and iden-
tify limitations of this Ir-catalyzed electrochemical vinylic C–
H annulation. As shown in Scheme 2, a variety of -
substituted acrylic acids all reacted well, affording the corre-
sponding -pyrones in good to excellent yields. Acrylic acids
substituted with various of functional groups such as alkyl,
ether, halides, trifluoromethyl, silyl, allyl, and ester groups
were well tolerated under the standard conditions (3a–3v).
The connectivities of 3b and 3r were unambiguously con-
firmed by X-ray analysis. Unsubstituted acrylic acid gave
good yield (3w). In contrast, -substituted acrylic acids gen-
erally give lower yields (3x–3ac). In these cases, partial unre-
acted alkynes can be observed after 12 h, however the acrylic
acids are normally fully consumed. Interestingly, the sub-
strate bearing methyl group at ,-positions results in good
yield (3ad).
1
2
3
4
5
6
7
8
transformation with Ir catalysis has not been realized to
date,27 presumably due to decarboxylation28 or difficulty of
dissociation of the Ir catalyst from the stable 18-electron
diene-Ir(I) complex that is formed during the course of the
reaction (Scheme 1B).29
Table 1. Reaction Optimization with Substrate 1aa,b
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Evaluation of Acrylic Acid Scopea
aReaction conditions: 1a (0.24 mmol), 2a (o.2 mmol),
(Cp*IrCl2)2 (3 mol%), n-Bu4NOAc (3.0 equiv) and MeOH (3
mL), in an undivided cell with two platinum electrodes (each
b
1.0 × 1.0 cm2), 60 °C, 1.5 mA, 12 h. The yield was determined
1
c
by H NMR using CH2Br2 as an internal standard. Isolated
d
yield in parentheses. The reaction was carried out with IKA
electraSyn 2.0 at room temperature (see Supporting Infor-
mation for details).
Initially, we chose 2-phenylacrylic acid (1a) and diphenyla-
cetylene (2a) as model substrates and probed various reac-
tion conditions in an undivided cell for the envisioned elec-
trochemical vinylic C–H annulation (Table 1, and see Table
S1–S5 in the Supporting Information). After extensive opti-
mization, we found that 95% isolated yield of -pyrone (3a)
could be obtained under constant-current electrolysis at 1.5
mA in the presence of 3 mol% of (Cp*IrCl2)2, and three equiv-
alents of n-Bu4NOAc in MeOH at 60 °C after 12 h (Table 1,
entry 1). The reactivity diminished significantly when other
solvents were used (entries 2–5). Increasing electric current
(entries 6 and 7) or deceasing the reaction temperature re-
sulted in slightly lower yields (entries 8 and 9). To our de-
light, the compatible yield was obtained when the reaction
was carried out with IKA ElectroSyn 2.0 at room temperature
(entry 10). Valuating different electrolytes revealed that ace-
tate anion is crucial for the reaction (entries 11–13). These
results might indicate that the deprotonation in C–H activa-
tion step is assisted by an acetate.30 It is worth noting that
chemical oxidants, including O2, Ag2CO3 and Cu(OAc)2 did
not give significant amounts of the desired product in the
absence of electrical current under otherwise identical condi-
aReaction conditions: 1a–1z (0.24 mmol), 2a (0.2 mmol),
(Cp*IrCl2)2 (3 mol%), n-Bu4NOAc (3.0 equiv) and MeOH (3
mL), in an undivided cell with two platinum electrodes (each
1.0 × 1.0 cm2), 60 °C, 1.5 mA, 12 h. bGram scale (see Supporting
Information for details).
ACS Paragon Plus Environment

Page 3 of 8
Journal of the American Chemical Society
Scheme 3. Evaluation of Alkyne Scopea
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: 1a or 1l (0.24 mmol), 4a–4r or 5a–5s (0.2 mmol), (Cp*IrCl2)2 (3 mol%), n-Bu4NOAc (3.0 equiv) and MeOH
b
(3 mL), in an undivided cell with two platinum electrodes (each 1.0 × 1.0 cm2), 60 °C, 1.5 mA, 12 h. Gram scale (see Supporting
Information for details).
Next, we moved on to investigate the reactivity of a series
of internal alkynes. As shown in Scheme 3, diarylacetylenes
with various functional groups, such as alkyl, ether, halides,
trifluoromethyl, cyano, and thiophene groups, were well tol-
erated, affording -pyrones in good to excellent yields (6a–
6n). In addition, dialkylacetylenes also resulted in good
yields (6o–6q). To our delight, excellent regioselectivity was
achieved with unsymmetrical alkynes, placing the aromatic
moiety in proximal to the oxygen heteroatom (7a–7o). Since
Co or Ru-catalyzed annulations of acrylic acids with unsym-
metrical internal alkynes are known,23a,24e Thus, we have also
included the yields and regioselectivities of annulation with
unsymmetrical internal alkynes for a direct comparison (see
Supporting Information for details). Generally speaking, Co-
catalyzed annulation with chemical oxidants results in 1:1~1:2
regioselectivities.23a Ru-catalyzed annulation with chemical
oxidants gives 1:1~4:1 regioselectivities.24e In contrast, our
electrochemical annulation results in 10:1~30:1 regioselectivi-
ties. This clearly demonstrates the advantage of our protocol
over Co or Ru-catalyzed annulation using chemical oxidants
to achieve highly selective regioselectivity with unsymmet-
rical internal alkynes. The structures of 6o, 7g, 7l and 7m
were unambiguously verified by X-ray analysis. Furthermore,
the developed protocol could be applied into the diversifica-
tion of natural products, showcasing the potential utility of
this chemistry (7p–7s).
To gain insight into the mechanism of this electrochemical
vinylic C–H annulation, we first investigated the stoichio-
metric reaction of acrylic acids, alkynes, and (IrCp*Cl2)2 in
the absence of electric current. Interestingly, in these cases
the iridium sandwich complexes 8a–8f could be obtained,
with the corresponding -pyrone serving as a neutral η4 lig-
and. Their structures were unambiguously confirmed by X-
ray analysis (Scheme 4). They are coordinatively saturated,
18-electron complexes, which explains their stability and
inertness towards chemical oxidants (e.g., Ag(I) or Cu(II)).
Next, complex 10 was synthesized by reacting
IrCp*(OAc)2(DMSO) complex 9 and substrate 1a at 60 °C for
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 8
4 h, and its structure was verified by X-ray analysis (Scheme
Figure 1. Cyclic voltammograms recorded on a Pt electrode
(area = 0.03 cm2), The scan rate was 100 mV s−1: (a) MeCN
containing 0.1 M n-Bu4NPF6; (b) MeCN containing 0.1 M n-
Bu4NPF6, after addition of 4 mM 1a; (c) MeCN containing 0.1
M n-Bu4NPF6, after addition of 4 mM 2a; (d) MeCN
containing 0.1 M n-Bu4NPF6, after addition of 4 mM 3a; (e)
MeCN containing 0.1 M n-Bu4NPF6, after addition of 4 mM
complex 8a; (f) MeCN containing 0.1 M n-Bu4NPF6, after
addition of 2 mM (Cp*IrCl2)2.
1
2
3
4
5
6
7
8
5A). Complex 8a was then obtained from by treating 10 with
alkyne 2a. Iridium complex 8a found to be a competent in-
termediate and catalyst in electrochemical vinylic C–H annu-
lation (Scheme 5B). Interestingly, treatment of 8a with repre-
sentative chemical oxidants Ag2CO3 an Cu(OAc)2 at 60 °C or
120 °C did not give significant amounts of product 3a. How-
ever, when 8a was subjected to electric current, 3a was
formed in 84% yield (Scheme 5C). Complex 8a, in a 0.1 M
solution of n-Bu4NPF6 in MeCN exhibits oxidation peaks at
0.98 and 1.72 V versus SCE (curve a, Figure 1).31 This result
indicates that 8a is oxidized preferentially under anodic oxi-
dation since the oxidation potentials of substrates (1a and 2a)
and product 3a are significantly higher than 8a (Figure 1).
9
Based on our mechanistic studies, we propose a plausible
catalytic cycle as shown in Scheme 6. Initially, C–H activa-
tion takes place to afford a cyclometallated Ir(III) intermedi-
ate B, following ligand exchange to deliver complex C. Next,
migratory alkyne insertion results in the seven-membered
iridium complex D,32 which undergoes reductive elimination
to give Ir(I) complex E. Intermediate E is a coordinatively
saturated, 18-electron complex. Upon anodic oxidation,
product 3a was realised from E and complex A is regenerated.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Stoichiometric Reactions
Scheme 6. Proposed Catalytic Cycle
Scheme 5. Mechanistic Study
In conclusion, we have demonstrated the first example of
Ir-catalyzed electrochemical vinylic C–H annulation of acryl-
ic acids with alkynes in an undivided cell. The method af-
fords a variety of -pyrones in good to excellent yields. Pre-
liminary mechanistic experiments show that anodic oxida-
tion is crucial for reoxidation of the diene-Ir(I) complex to an
Ir(III) species with concomitant release of the product. Addi-
tional work on electrochemical vinylic C–H functionalization
is currently underway in our laboratory.
ASSOCIATED CONTENT
Supporting Information
Text, Figures, Tables, and CIF files giving experimental pro-
cedure, compound characterization data, and crystallograph-
ic data. This material is available free of charge via the Inter-
net at http://pubs.acs.org.
2.5x10-4
a blank
2.77 V
b 1a
f
2.0x10-4
c 2a
d 3a
2.02 V
1.99 V
1.73 V
1.72 V
e 8a
1.5x10-4
1.0x10-4

f (Cp IrCl
)
2
2
2.49 V
c
AUTHOR INFORMATION
b
0.98 V
d
5.0x10-5
0.0
e
Corresponding Author
a
Mei7900@sioc.ac.cn
Author Contributions
§Q.-L. Y. and Y.-K. X. contributed equally to this work.
-5.0x10-5
0.0
0.5
1.0
1.5
E (V) vs SCE
2.0
2.5
3.0
ACS Paragon Plus Environment

Page 5 of 8
Journal of the American Chemical Society
Bercaw, J. E. Electrocatalytic functionalization of alkanes using
Notes
1
2
3
4
5
6
7
8
aqueous platinum salts. J. Mol. Catal. 1994, 87, L11–L15.
The authors declare no competing financial interests.
(10) For selected examples see: (a) Yang, Q.-L.; Li, C.-Z.; Zhang, L.-
W.; Li, Y.-Y.; Tong, X.; Wu, X.-Y.; Mei, T.-S. Palladium-Catalyzed
Electrochemical C–H Alkylation of Arenes. Organometallics 2019, 38,
1208–1212. (b) Dudkina, Y. B.; Mikhaylov, D. Y.; Gryaznova, T. V.;
Tufatullin, A. I.; Kataeva, O. N.; Vicic, D. A.; Budnikova, Y. H.
Electrochemical Ortho Functionalization of 2-Phenylpyridine with
Perfluorocarboxylic Acids Catalyzed by Palladium in Higher
Oxidation States. Organometallics 2013, 32, 4785–4792. (c) Kakiuchi,
F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano, S.; Sato, M.;
Nishiyama, S.; Tanabe, T. Palladium-Catalyzed Aromatic C−H Halo-
genation with Hydrogen Halides by Means of Electrochemical Oxi-
dation. J. Am. Chem. Soc. 2009, 131, 11310–11311. (d) Amatore, C.;
Cammoun, C.; Jutand, Electrochemical Recycling of Benzoquinone
in the Pd/Benzoquinone-Catalyzed Heck-Type Reactions from
Arenes. Adv. Synth. Catal. 2007, 349, 292–296.
(11) Budkina, Y. B.; Mikhaylov, D. Y.; Gryaznova, T. V.; Sinyashin, O.
G.; Vicic, D. A.; Budnikova, Y. H. MII/MIII-Catalyzed ortho-
Fluoroalkylation of 2-Phenylpyridine. Eur. J. Org. Chem. 2012, 2114–
2117.
(12) For selected examples, see: (a) Sauermann, N.; Mei, R.; Acker-
mann, L. Electrochemical C−H Amination by Cobalt Catalysis in a
Renewable Solvent. Angew. Chem. Int. Ed. 2018, 57, 5090–5094. (b)
Gao, X.; Wang, P.; Zeng, L.; Tang, S.; Lei, A. Cobalt (II)-Catalyzed
Electrooxidative C–H Amination of Arenes with Alkylamines. J. Am.
Chem. Soc. 2018, 140, 4195–4199. (c) Sauermann, N.; Meyer, T. H.;
Tian, C.; Ackermann, L. Electrochemical Cobalt-Catalyzed C–H
Oxygenation at Room Temperature. J. Am. Chem. Soc. 2017, 139,
18452–18455.
(13) (a) Luo, M.-J. Zhang, T.-T.; Cai, F.-J.; Li, J.-H.; He, D.-L. Decar-
boxylative [4+2] annulation of arylglyoxylic acids with internal al-
kynes using the anodic ruthenium catalysis. Chem. Commun. 2019,
55, 7251–7254. (b) Luo, M.-J.; Hu, M.; Song, R.-J.; He, D.-L.; Li, J.-H.
Ruthenium(II)-catalyzed electrooxidative [4+2] annulation of ben-
zylic alcohols with internal alkynes: entry to isocoumarins. Chem.
Commun. 2019, 55, 1124–1127. (c) Mei, R.; Koller, J.; Ackermann, L.
Electrochemical ruthenium-catalyzed alkyne annulations by C–
H/Het–H activation of aryl carbamates or phenols in protic media.
Chem. Commun. 2018, 54, 12879–12882. (d) Qiu, Y.; Kong, W.-J.;
Struwe, J.; Sauermann, N.; Rogge,T.; Scheremetjew, A.; Ackermann,
L. Electrooxidative Ruthenium-Catalyzed C–H/O–H Annulation by
Weak O-Coordination. Angew. Chem. Int. Ed. 2018, 57, 5818–5822. (e)
Xu, F.; Li, Y.-J.; Huang, C.; Xu, H.-C. Ruthenium-Catalyzed Electro-
chemical Dehydrogenative Alkyne Annulation. ACS Catal. 2018, 8,
3820–3824.
(14) (a) Tian, C.; Dhawa, U.; Scheremetjew, A.; Ackermann, L. Cu-
praelectro-Catalyzed Alkyne Annulation: Evidence for Distinct C–H
Alkynylation and Decarboxylative C–H/C–C Manifolds. ACS Catal.
2019, 9, 7690–7696. (b) Kathiravan, S.; Suriyanarayanan, S.; Nicholls.
I. A. Electrooxidative Amination of sp2 C–H Bonds: Coupling of
Amines with Aryl Amides via Copper Catalysis. Org. Lett. 2019, 21,
1968–1972. (c) Yang, Q.-L.; Wang, X.-Y.; Lu, J.-Y.; Zhang, L.-P.; Fang,
P.; Mei, T.-S. Copper-Catalyzed Electrochemical C–H Amination of
Arenes with Secondary Amines. J. Am. Chem. Soc. 2018, 140, 11487–
11494.
ACKNOWLEDGMENT
This work was financially supported by the Strategic Priority
Research Program of the Chinese Academy of Sciences
(Grant XDB20000000), NSF of China (Grant 21772222,
21821002), and S&TCSM of Shanghai (Grant 17JC1401200,
18JC1415600).
9
REFERENCES
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(1) For recent selective reviews on organic electrochemistry, see: (a)
Sauer, G. S.; Lin, S. An electrocatalytic approach to the radical
difunctionalization of alkenes. ACS Catal. 2018, 8, 5175–5187. (b)
Waldvogel, S. R.; Lips, S.; Selt, M.; Riehl, B.; Kampf, C. J.
Electrochemical arylation reaction. Chem. Rev. 2018, 118, 6706–6765.
(c) Moeller, K. D. Using physical organic chemistry to shape the
course of electrochemical reactions. Chem. Rev. 2018, 118, 4817–4833.
(d) Jiang, Y.; Xu, K.; Zeng, C. Use of electrochemistry in the synthesis
of heterocyclic structures. Chem. Rev. 2018, 118, 4485–4540. (e) Yan,
M.; Kawamata, Y.; Baran, P. S. Synthetic organic electrochemical
methods since 2000: on the verge of a renaissance. Chem. Rev. 2017,
117, 13230–13319.
(2) (a) Horn, E. J.; Rosen, B. R.; Baran, P. S. Synthetic Organic
Electrochemistry: An Enabling and Innately Sustainable Method.
ACS Cent. Sci. 2016, 2, 302–308. (b) Yoshida, J.-i.; Kataoka, K.; Horca-
jada, R.; Nagaki, A. Modern Strategies in Electroorganic Synthesis.
Chem. Rev. 2008, 108, 2265–2299.
(3) For selected reviews on electrochemical C–H functionalization,
see: (a) Wiebe, A.; Gieshoff, T.; Möhle, S.; Rodrigo, E.; Zirbes, M.;
Waldvogel, S. R. Electrifying Organic Synthesis. Angew. Chem., Int.
Ed. 2018, 57, 5594–5619. (b) Tang, S.; Zeng, L.; Lei, A. Oxidative R1–H
/R2–H Cross-Coupling with Hydrogen Evolution. J. Am. Chem. Soc.
2018, 140, 13128-13135. (c) Tang, S.; Liu, Y.; Lei, A. Electrochemical
Oxidative Cross-coupling with Hydrogen Evolution: A Green and
Sustainable Way for Bond Formation. Chem 2018, 4, 27–45. (d) Yang,
Q.-L.; Fang, P.; Mei, T.-S. Recent Advances in Organic
Electrocehmical C–H Functionalization. Chin. J. Chem. 2018, 36, 338–
352. (e) Hou, Z.-W.; Mao, Z.-Y.; Xu, H.-C. Recent Progress on the
Synthesis of (Aza) indoles through Oxidative Alkyne Annulation
Reactions. Synlett 2017, 28, 1867–1872.
(4) (a) Nutting, J. E.; Rafiee, M.; Stahl, S. S. Tetramethyhlpiperidine
N-Oxyl (TEMPO), Phthalimide N-Oxyl (PINO), and Related N-Oxy
Species: Electrochemical Properties and Their Use in Electrocatalytic
Reactions. Chem. Rev. 2018, 118, 4834–4885. (b) Francke, R.; Little, R.
D. Redox catalysis in organic electrosynthesis: basic principles and
recent developments. Chem. Soc. Rev. 2014, 43, 2492–2521.
(5) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.; Eastgate, M.
D.; Baran, P. S. Scalable and sustainable electrochemically allylic C–
H oxidation. Nature 2016, 533, 77–81.
(6) Kawamata, Y.; Yan, M.; Liu, Z.; Bao, D.-H.; Chen, J.; Starr, J. T.;
Baran, P. S. Scalable, Electrochemical Oxidation of Unactivated C–H
Bonds. J. Am. Chem. Soc. 2017, 139, 7448–7451.
(7) Yang, Q.-L.; Li, Y.-Q.; Ma, C.; Fang, P.; Zhang, X.-J.; Mei, T.-S.
Palladium-Catalyzed C(sp3)–H Oxygenation via Electrochemical
Oxidation. J. Am. Chem. Soc. 2017, 139, 3293–3298.
(8) Shrestha, A.; Lee, M.; Dunn, A. L.; Sanford, M. S. Palladium-
Catalyzed C–H Bond Acetoxylation via Electrochemical Oxidation.
Org. Lett. 2018, 20, 204–207.
(15) (a) Kong, W.-J.; Finger, L. H.; Messinis, A. M.; Kuniyil, R.;
Oliveira, J. C. A.; Ackermann, L. Flow Rhodaelectro-Catalyzed Al-
kyne Annulations by Versatile C–H Activation: Mechanistic Support
for Rhodium(III/IV). J. Am. Chem. Soc. 2019, 141, 17198–17206. (b) Qiu,
Y.; Scheremetjew, A.; Ackermann, L. Electrooxidative C–C Alkenyla-
tion by Rhodium(III) Catalysis. J. Am. Chem. Soc. 2019, 141, 2731–2738.
(9) For the early example of Pt-catalyzed electrochemical benzylic
C–H functionalization, see: Freund, M. S.; Labinger, J. A.; Lewis, N. S.;
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 8
(c) Kong, W.-J.; Finger, L. H.; Oliveira, J. C. A.; Ackermann, L.
Sen, M.; Mandal, R.; Das, A.; Kalsi, D.; Sundararaju, B. Cp*CoIII–
Catalyzed Bis-isoquinolone Synthesis by C–H Annulation of Aryla-
mide with 1,3-Diyne. Chem. Eur. J. 2017, 23, 17454–17457. (c) Grigor-
jeva, L.; Daugulis, O. Cobalt-Catalyzed, Aminoquinoline-Direted
C(sp2)–H Bond Alkenylation by Alkynes. Angew. Chem. Int. Ed. 2014,
53, 10209–10212.
1
2
3
4
5
6
7
8
Rhodaelectrocatalysis for Annulative C–H Activation: Polycyclic
Aromatic Hydrocarbons by Versatile Double Electrocatalysis. Angew.
Chem. Int. Ed. 2019, 58, 6342–6346.
(16) Qiu, Y.; Stangier, M.; Meyer, T. H.; Oliveira, J. C. A.; Ackermann,
L. Iridium-Catalyzed Electrooxidative C−H Activation by Chemose-
lective Redox-Catalyst Cooperation. Angew. Chem. Int. Ed. 2018, 57,
14179–14183.
(24) For selected reviews, see: (a) Duarah, G.; Kaishap, P. P.; Begum,
T.; Gogoi, S. Recent Advances in Ruthenium(II)-Catalyzed C–H Bond
Activation and Alkyne Annulation Reactions. Adv. Synth. Catal. 2019,
361, 654–672. (b) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Ruthe-
nium(II)-Catalyzed C–H Bond Activation and Functionalization.
Chem. Rev. 2012, 112, 5879–5918. For selected examples, see: (c) Pra-
kash, R.; Shekarrao, K.; Gogoi, S. Ruthenium(II)-Catalyzed Alkene
C−H Bond Functionalization on Cinnamic Acids: A Facile Synthesis
of Versatile α-Pyrones. Org. Lett. 2015, 17, 5264−5267. (d) Chin-
nagolla, R. K.; Jeganmohan, M. Regioselective synthesis of isocouma-
rins by ruthenium-catalyzed aerobic oxidative cyclization of aro-
matic acids with alkynes. Chem. Commun. 2012, 48, 2030–2032. (e)
Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K. Versatile Synthe-
sis of Isocoumarins and -Pyrones by Ruthenium-Catalyzed Oxida-
tive C–H/O–H Bond Cleavages. Org. Lett. 2012, 14, 930–933. (f)
Ackermann, L.; Lygin, A. V.; Hofmann, N. Ruthenium-Catalyzed
Oxidative Synthesis of 2-Pyridones through C–H/N–H Bond Func-
tionalizations. Org. Lett. 2011, 13, 3278–3281.
(25) For selected reviews, see: (a) Yang, Y.; Li, K.; Cheng, Y.; Wan, D.;
Li, M.; You, J. Rhodium-catalyzed annulation of arenes with alkynes
through weak chelation-assisted C–H activation. Chem. Commun.
2016, 52, 2872–2884. (b) Song, G.; Wang, F.; Li, X. C–C, C–O and C–N
bond formation via rhodium(III)-catalyzed oxidative C–H activation.
Chem. Soc. Rev. 2012, 41, 3651–3678. (c) Satoh, T.; Miura, M. Oxida-
tive Coupling of Aromatic Substrates with Alkynes and Alkenes un-
der Rhodium Catalysis. Chem. Eur. J. 2010, 16, 11212–11222. For select-
ed examples, see: (d) Kudo, E.; Shibata, Y.; Yamazaki, M.; Masutomi,
K.; Miyauchi, Y.; Fukui, M.; Sugiyama, H.; Uekusa, H.; Satoh, T.;
Miura, M.; Tanaka, K. Oxidative Annulation of Arenecarboxylic and
Acrylic Acids with Alkynes under Ambient Conditions Catalyzed by
an Electron Deficient Rhodium(III) Complex. Chem. Eur. J. 2016, 22,
14190–14194. (e) Li, Q.; Yan, Y.; Wang, X.; Gong, B.; Tang, X.; Shi, J.;
Xu, H. E.; Yi, W. Water as a green solvent for efficient synthesis of
isocoumarins through microwave-accelerated and Rh/Cu-catalyzed
C–H/O–H bond functionalization. RSC Adv. 2013, 3, 23402–23408. (f)
Itoh, M.; Shimizu, M.; Hirano, K.; Satoh, T.; Miura, M. Rhodium-
Catalyzed Decarboxylative and Dehydrogenative Coupling of Maleic
Acids with Alkynes and Alkenes. J. Org. Chem. 2013, 78, 11427−11432.
(g) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. Synthesis of Func-
tionalization Pyrone and Butenolide Derivatives by Rhodium-
Catalyzed Oxidative Coupling of Substituted Acrylic Acids with Al-
kynes and Alkenes. J. Org. Chem. 2009, 74, 6295–6298.
(17) For selected reviews on metal-catalyzed electrochemical C–H
functionalization, see: (a) Qiu, Y.; Struwe, J.; Ackermann, L. Metal-
laelectro-Catalyzed C–H Activation by Weak Coordination. Synlett
2019, 30, 1164–1173. (b) Meyer, T. H.; Finger, L. H.; Gandeepan, P.;
Ackermann, L. Resource Economy by Metallaelectrocatalysis: Merg-
ing Electrochemistry and C–H Activation. Trends Chem. 2019, 1, 63–
76. (c) Sauermann, N.; Meyer, T. H.; Qiu, Y.; Ackermann, L.
Electrocatalytic C–H Activation. ACS Catal. 2018, 8, 7086–7103. (d)
Sauermann, N.; Meyer, T. H.; Ackermann, L. Electrochemical Cobalt-
Catalyzed C-H Activation. Chem. Eur. J. 2018, 24, 16209–16217. (e) Ma,
C.; Fang, P.; Mei, T.-S. Recent advances in C–H functionalization
using electrochemical transition metal catalysis. ACS Catal. 2018, 8,
7179–7189. (f) Budkina, Y. B.; Gryaznova, T. V.; Sinyashin, O. G.;
Budnikova, Y. H. Russ. Chem. Bull., Int. Ed. 2015, 64, 1713–1725.
(18) For selected examples on metal-catalyzed electrochemical arene
C–H/O–H or C–H/N–H annulation, see: (a) Mei, R.; Ma, W.; Zhang,
Y.; Guo, X.; Ackermann, L. Cobaltaelectro-Catalyzed Oxidative
C−H/N−H Activation with 1,3-diynes by Electro-Removable Hydra-
zides. Org. Lett. 2019, 21, 6534–6538. (b) Meyer, T. H.; Oliveira, J. C.
A.; Sau, S. C.; Ang, N. W. J.; Ackermann, L. Electrooxidative Allene
Annulations by Mild Cobalt-Catalyzed C–H Activation. ACS Catal.
2018, 8, 9140–9147. (c) Mei, R.; Sauermann, N.; Oliveira, J. C. A.;
Ackermann, L. Electroremovable Traceless Hydrazides for Cobalt-
Catalyzed Electro-Oxidative C–H/N–H Activation with Internal Al-
kynes. J. Am. Chem. Soc. 2018, 140, 7913–7921. (d) Tian, C.; Massignan,
L.; Meyer, T. H.; Ackermann, L. Electrochemical C–H/N–H
Activation by water-Tolerant Cobalt-Catalysis at Room Temperature.
Angew. Chem. Int. Ed. 2018, 57, 2383–2387. (e) Tang, S.; Wang, D.; Liu,
Y.; Liu, L.; Lei, A. Cobalt-catalyzed electrooxidative C-H/N-H [4+2]
annulation with ethylene or ethyne. Nature Commun. 2018, 9, 798–
805. (f) Reference 13.
(19) Qiu, Y.; Kong, W.-J.; Struwe, J.; Sauermann, N.; Rogge, T.
Scheremetjew, A.; Ackermann, L. Electrooxidative Rhodium-
Catalyzed C–H/C–H Activation: Electricity as Oxidant for Cross-
Dehydrogenative Alkenylation. Angew. Chem. Int. Ed. 2018, 57, 5828–
5832.
(20) For selected recent reviews on metal-catalyzed vinylic C–H
functionalization, see: (a) Maraswami, M.; Loh, T.-P. Transition-
Metal-Catalyzed Alkenyl sp2 C–H Activation: A Short Account. Syn-
thesis 2019, 51, 1049–1062. (b) Liu, M.; Yang, P.; Karunananda, M. K.;
Wang, Y.; Liu, P.; Engle, K. M. C(alkenyl)–H Activation via Six-
Membered Palladacyles: Catalytic 1,3-Diene Synthesis. J. Am. Chem.
Soc. 2018, 140, 5805–5813. (c) Wang, K.; Hu, F.; Zhang, Y.; Wang, J.
Directing group-assisted transition-metal-catalyzed vinylic C–H
bond functionalization. Sci. China. Chem. 2015, 58, 1252–1265. (d)
Shang, X.; Liu, Z.-Q. Transition Metal-catalyzed Cvinyl–H bond activa-
tion. Chem. Soc. Rev. 2013, 42, 3253–3260.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(26) (a) Sun, Y.; Zhang, G. Palladium-Catalyzed Formal [4+2] Cy-
cloaddition of Benzoic and Acrylic Acids with 1,3-Dienes via C–H
Bond Activation: Efficient Access to 3,4-Dihydroisocoumarin and
5,6-Dihydrocoumalins. Chin. J. Chem. 2018, 36, 708–711. (b) Yu, Y.;
Huang, L.; Wu, W.; Jiang, H. Palladium-Catalyzed Oxidative Annula-
tion of Acrylic Acid and Amide with Alkynes: A Practical Route to
Synthesize -Pyrones and Pyridones. Org. Lett. 2014, 16, 2146–2149.
(27) For selected examples on Ir-catalyzed vinylic C–H functionaliza-
tion, see: (a) Sun, Y.; Meng, K.; Zhang, J.; Jin, M.; Huang, N.; Zhong,
G. Additive- and Ligand-Free Cross-Coupling Reactions between
Alkenes and Alkynes by Iridium Catalysis. Org. Lett. 2019, 21, 4868–
4872. (b) Kim, H.; Park, G.; Park, J.; Chang, S. A Facile Access to
Primary Alkylamines and Anilines via Ir(III)-Catalyzed C–H Ami-
dation by Using Azidoformates. ACS Catal. 2016, 6, 5922–5929. (c)
(21) Blanksby, S. J.; Ellison, G. B. Bond dissociation energies of organ-
ic molecules. Acc. Chem. Res. 2003, 36, 255–263.
(22) (a) Schäberle, T. F. Biosynthesis of -pyrones. Beilstein J. Org.
Chem. 2016, 12, 571–588. (b) Lee, J. S. Recent Advances in the Synthe-
sis of 2-Pyrones. Mar. Drugs 2015, 13, 1581–1620.
(23) (a) Mandal, R.; Sundararaju, B. Cp*Co(III)-Catalyzed Annulation
of Carboxylic Acids with Alkynes. Org. Lett. 2017, 19, 2544–2547. (b)
ACS Paragon Plus Environment

Page 7 of 8
Journal of the American Chemical Society
Sasaki, I.; Taguchi, J.; Doi, H.; Ito, H.; Ishiyama, T. Iridium(I)-
1
2
3
4
catalyzed C−H Borylation of α,β-Unsaturated Esters with
Bis(pinacolato)diboron. Chem. - Asian J. 2016, 11, 1400–1405. (d) Zhou,
J.; Hartwig, J. F. Iridium-Catalyzed H/D Exchange at Vinyl Groups
without Olefin Isomerization. Angew. Chem. Int. Ed. 2008, 47, 5783–
5787.
5
(28) For selected examples on Ir-catalyzed arene C–H annulation,
see: (a) Datsenko, V. P.; Nelyubina, Y. V.; Smol’yakov, A. F.; Loginov,
D. A. Cyclooctadiene iridium complexes [Cp*Ir(COD)X]+ (X = Cl, Br,
I): Synthesis and application for oxidative coupling of benzoic acid
with alkynes. J. Organometal. Chem. 2018, 874, 7–12. (b) Ueura, K.;
Satoh, T.; Miura, M. Rhodium- and Iridium-Catalyzed Oxidative
Coupling of Benzoic Acids with Alkynes via Regioselective C–H Bond
Cleavage. J. Org. Chem. 2007, 72, 5362–5367.
(29) Han, Y.-F.; Jin, G.-X. Cyclometalated [Cp*M(C^X)] (M = Ir, Rh; X
= N. C, O, P) complexes. Chem. Soc. Rev. 2014, 43, 2799–2783.
(30) (a) Davies, D. L.; Macgregor, S. A.; McMullin, C. L. Computa-
tional Studies of Carboxylate-Assisted C–H Activation and Function-
alization at Group 8–10 Transition Metal Centers. Chem. Rev. 2017,
117, 8649–8709. (b) Frasco, D. A.; Lilly, C. P.; Boyle, P. D.; Ison, E. A.
Cp*IrIII-Catalyzed Oxidative Coupling of Benzoic Acids with Alkynes.
ACS Catal. 2013, 3, 2421–2429. (c) Ackermann, L. Carboxylate-
Assisted Transition-Metal-Catalyzed C–H Bond Functionalizations:
mechanism and Scope. Chem. Rev. 2011, 111, 1315–1345.
(31) Shin, K.; Park, Y.; Baik, M.-H.; Chang, S. Iridium-catalyzed aryla-
tion of C–H bonds enabled by oxidatively induced reductive elimina-
tion. Nature Chem. 2018, 10, 218–224.
(32) (a) Han, Y.-F.; Li, H.; Hu, P.; Jin, G.-X. Alkyne Insertion Induced
Regiospecific C–H Activation with [Cp*MCl2]2 (M = Ir, Rh). Organo-
metallic 2011, 30, 905–911. (b) Li, L.; Brennessel, W. W.; Jones, W. D.
An Efficient Low-Temperature Route to Polycyclic Isoquinoline Salt
Synthesis via C–H Activation with [Cp*MCl2]2 (M = Rh, Ir). J. Am.
Chem. Soc. 2008, 130, 12414–12419.
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 8
Table of Contents
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
ACS Paragon Plus Environment